WO2020071349A1 - Médicament combiné comprenant une composition de liposome encapsulant un médicament et préparation à base de platine - Google Patents

Médicament combiné comprenant une composition de liposome encapsulant un médicament et préparation à base de platine

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Publication number
WO2020071349A1
WO2020071349A1 PCT/JP2019/038708 JP2019038708W WO2020071349A1 WO 2020071349 A1 WO2020071349 A1 WO 2020071349A1 JP 2019038708 W JP2019038708 W JP 2019038708W WO 2020071349 A1 WO2020071349 A1 WO 2020071349A1
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WIPO (PCT)
Prior art keywords
liposome
drug
aqueous phase
topotecan
liposome composition
Prior art date
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Ceased
Application number
PCT/JP2019/038708
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English (en)
Japanese (ja)
Inventor
岡田　健
晋 下山
幹永 森
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Fujifilm Corp
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Fujifilm Corp
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Filing date
Publication date
Application filed by Fujifilm Corp filed Critical Fujifilm Corp
Priority to EP19869479.6A priority Critical patent/EP3861987A4/fr
Priority to JP2020550444A priority patent/JP7057434B2/ja
Priority to CN201980064960.5A priority patent/CN112789032A/zh
Publication of WO2020071349A1 publication Critical patent/WO2020071349A1/fr
Priority to US17/219,064 priority patent/US12370214B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a medicament administered simultaneously or sequentially in combination with a liposome composition containing a drug and a platinum preparation.
  • Patent Document 1 and Non-Patent Document 1 describe liposomes in which topotecan is encapsulated in liposomes containing sphingomyelin and cholesterol.
  • Patent Document 2 describes a liposome in which topotecan is encapsulated in a liposome containing dihydrosphingomyelin and cholesterol.
  • U.S. Patent No. 6,064,086 discloses a liposomal camptothecin formulation adapted to enhance the stability of camptothecin, wherein (a) camptothecin encapsulated in the liposome, (b) outside the liposome, and has a pH of less than 4.5 or 4. A formulation comprising a first solution of 5 and (c) a second solution inside the liposome is described. It is also described that the liposome contains dihydrosphingomyelin and cholesterol.
  • Patent Document 4 discloses a system for effectively filling an liposome with an amphiphilic drug, in which a liposome suspension is prepared in the presence of an ammonium compound or an ammonium salt, and the suspension is diluted with a buffer or a salt. And providing between the inner aqueous phase and the outer aqueous phase an ammonium gradient going from the inside to the outside and a pH gradient such that the pH inside the liposome is more acidic than the outside pH. The system has been described.
  • Patent Document 5 describes a liposome in which topotecan is encapsulated in a liposome containing purified hydrogenated soybean phospholipid or sphingomyelin, cholesterol, and a hydrophilic polymer derivative lipid in the presence of ammonium sulfate.
  • Non-Patent Document 2 shows that the combination of SN-38, an active metabolite of irinotecan (a topoisomerase I inhibitor, CPT-11), and oxaliplatin inhibited tumor growth more than twice as high as oxaliplatin alone. It is described.
  • Patent Documents 1, 2, and 3 and Non-Patent Document 1 disclose that topotecan or camptothecin is contained in a liposome containing sphingomyelin or dihydrosphingomyelin, thereby suppressing the outflow of topotecan in blood, and AUC ( It describes that the drug efficacy is improved by improving the area under the blood concentration-time curve (area under the blood concentration-time curve).
  • AUC area under the blood concentration-time curve
  • the lipid composition of the liposome and the composition of the salt for precipitating topotecan have not been optimized, the AUC has not been sufficiently improved, and further improvement is required.
  • An object of the present invention is to provide a combination of two or more anticancer agents that act by different mechanisms in combination with a liposome composition containing a drug and a platinum preparation, and that the therapeutic effect is high and that two or more kinds of side effects are reduced. It is to provide a combination of anticancer agents.
  • a liposome composition comprising, as constituents of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug, A medicament which is administered simultaneously or sequentially in combination with a liposome composition and a (B) platinum formulation, wherein the phase comprises ammonium sulfate and the molar ratio of inner aqueous phase sulfate ions to total aqueous phase drug is 0.36 or more.
  • the present invention has been completed by finding out that
  • a liposome composition comprising (A) a diacylphosphatidylethanolamine modified with a hydrophilic polymer, dihydrosphingomyelin, and cholesterol as components of a liposome membrane, wherein the liposome composition contains a drug.
  • [5] The medicament according to any one of [1] to [4], wherein a ratio of diacylphosphatidylethanolamine modified with a hydrophilic polymer in a component of the liposome membrane is 2 to 10 mol%.
  • [8] The medicament according to any one of [1] to [7], wherein the pH of the outer aqueous phase is 5.5 to 8.5.
  • the dihydrosphingomyelin according to any one of [1] to [8], wherein the dihydrosphingomyelin is a dihydrosphingomyelin containing a long-chain alkyl group having 16 or 18 carbon atoms, and the encapsulated drug is topotecan or a salt thereof. Medicine.
  • the release rate of the drug from the liposome in plasma having an ammonium concentration of 1 mmol / L or less is 20% / 24 hours or less at 37 ° C., and the drug release rate from the liposome in the plasma having an ammonium concentration of 4 to 6 mmol / L.
  • the platinum preparation contains at least one selected from carboplatin, cisplatin, oxaliplatin and nedaplatin.
  • the administration is a dosage and administration period in which the administration shows a therapeutically synergistic effect.
  • a method for treating a disease (preferably cancer) of a subject wherein (A) a hydrophilic polymer is used as a component of the liposome membrane in an effective dose and administration period in which the subject has therapeutic synergy.
  • a liposome composition comprising diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with liposome, wherein the liposome composition contains a drug, the internal aqueous phase contains ammonium sulfate, and the internal aqueous phase relative to the total aqueous phase drug.
  • Diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer are used as components of the liposome membrane (A) for use in the treatment of a target disease (preferably cancer).
  • a liposome composition comprising a drug, wherein the liposome composition contains a drug, the internal aqueous phase contains ammonium sulfate, and the molar ratio of internal aqueous phase sulfate ions to all aqueous phase drugs is 0.36 or more.
  • a medicament administered simultaneously or sequentially in combination with a platinum preparation (A) a liposome composition comprising, as constituents of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug, Use of a medicament administered simultaneously or sequentially in combination with a liposome composition and (B) a platinum formulation, wherein the phase comprises ammonium sulfate and the molar ratio of internal aqueous sulfate to total aqueous drug is 0.36 or greater.
  • a liposome composition comprising, as constituent components of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug.
  • the inner aqueous phase comprises an ammonium salt and the dihydrosphingomyelin is a dihydrosphingomyelin having a long-chain alkyl group having 16 and 18 carbon atoms, wherein the liposome composition and the (B) platinum preparation are simultaneously or sequentially combined. Medication to be administered.
  • a liposome composition comprising, as constituent components of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer, wherein the liposome composition contains a drug.
  • the medicament of the present invention has at least one effect of treating or preventing cancer by being administered simultaneously or sequentially in combination with a liposome composition and a platinum preparation. Further, since the medicament of the present invention has a tumor growth inhibitory effect even at a low dose, it is desirable that, for subjects including patients, not only safety is high, but also the physical burden is low and the convenience is high. Be able to treat.
  • FIG. 1 shows a survival curve in a drug efficacy test using an A2780 subcutaneously transplanted tumor-bearing mouse model.
  • FIG. 2 shows a survival curve in a drug efficacy test using an A2780 subcutaneously transplanted tumor-bearing mouse model.
  • % means percent by mass.
  • amount of each component in the composition means the total amount of the plurality of substances present in the composition when there are a plurality of substances corresponding to each component in the composition, unless otherwise specified. I do.
  • “-” Indicates a range including numerical values described before and after it as a minimum value and a maximum value, respectively.
  • Subjects include humans and non-human mammals. Examples of mammals other than humans include monkeys, dogs, cats, cows, horses, mice, rats, and the like.
  • the treatment can be any treatment and therapy that achieves the desired therapeutic effect, eg, inhibiting or delaying progression of the condition, slowing progression, halting the speed of progression, reversing the condition, curing the condition. Or remission (whether partial or complete), prevention, delay, reduction or cessation of one or more symptoms and / or signs of the condition, or treatment of the subject or the subject's survival Is longer than expected in the absence of
  • Treatment also includes prevention.
  • treating a subject susceptible to or at risk for developing or recurring cancer can prevent or delay the onset or recurrence of cancer in the subject.
  • Treatment can include inhibiting cancer growth, including complete cancer remission, and / or inhibiting cancer metastasis.
  • Cancer growth refers to the change in cancer to a more developed form. Decrease in cancer cell survival, decrease in tumor volume or morphology (eg, using computed tomography (CT), ultrasonography, or other imaging modalities) to measure inhibition of cancer growth Tumor growth retardation, disruption of tumor vasculature, improved performance of delayed-type hypersensitivity skin tests, increased cytolytic T-lymphocyte activity, and levels of tumor-specific antigens And the like.
  • CT computed tomography
  • tumors malignant tumors, cancers, malignant neoplasms, carcinomas, sarcomas and the like are collectively referred to as “tumor” or “cancer”. “Tumor” or “cancer” also includes those that have recurred after being treated for cancer. “Tumor” includes all malignant or benign neoplastic cell growth and proliferation, as well as precancerous and cancerous cells and tissues.
  • Effective amount is the dosage required to achieve the desired therapeutic or prophylactic result, including the amount and duration of administration.
  • An “effective amount” of a medicament of the invention can vary according to the disease state, age, sex, and weight of the subject (or individual), the ability of the medicament to elicit the desired response in the subject (or individual), and the like.
  • “Simultaneous administration” refers to administration of a first therapy and a second therapy in a combination therapy for a time interval of about 15 minutes, such as any of about 10 minutes, about 5 minutes, or about 1 minute. Means to do. If the first therapy and the second therapy are administered simultaneously, the first therapy and the second therapy may be in the same composition (eg, a composition comprising both the first therapy and the second therapy). It can be included, or can be included in a separate composition (eg, the first therapy can be included in one composition and the second therapy can be included in another composition).
  • sequential administration refers to administering the first therapy and the second therapy in a combination therapy for about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes or longer (one day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, etc.).
  • the sequential administration can include administering the first therapy first, and also administering the second therapy first.
  • the sequential administration also includes performing the second therapy after performing the first therapy (after a predetermined time (for example, one week)).
  • the first therapy and the second therapy can be contained in separate compositions, and can be contained in the same package or kit, or can be contained in different packages or kits.
  • Retention in blood means a property of a drug administered to a liposome composition in which a drug encapsulated in liposome is present in blood.
  • Average particle size of liposome means an average particle size (preferably a cumulant average particle size) measured by a dynamic light scattering method unless otherwise specified.
  • Examples of commercially available measuring devices using dynamic light scattering include a concentrated particle analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.), Nanotrac UPA (manufactured by Nikkiso Co., Ltd.), and a Nanosizer (manufactured by Malvern). It is also possible to calculate the volume average particle diameter and the number average particle diameter of the liposome by a conversion formula specific to the measuring device of each manufacturer. When measuring particles near 100 nm, the distribution of particles cannot be accurately detected by a static light scattering method or the like, and measurement by a dynamic light scattering method is preferable.
  • the first form of the medicament of the present invention (A) a liposome composition comprising, as constituents of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug, A medicament administered simultaneously or sequentially in combination with a liposome composition and a (B) platinum formulation, wherein the phase comprises ammonium sulfate and the molar ratio of internal aqueous sulfate to total aqueous drug is 0.36 or greater.
  • the second form of the medicament of the present invention comprises: (A) a liposome composition comprising, as constituents of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug,
  • the liposome composition and the (B) platinum formulation are administered simultaneously or sequentially wherein the phase comprises an ammonium salt and the dihydrosphingomyelin is a dihydrosphingomyelin having a long chain alkyl group having 16 and 18 carbon atoms It is a medicine.
  • the third form of the medicament of the present invention comprises: (A) A liposome composition comprising, as constituent components of a liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer, wherein the liposome composition contains a drug. And (B) a medicament administered simultaneously or sequentially in combination with a platinum preparation.
  • the present invention applies to the first to third aspects of the medicament of the present invention.
  • the present invention includes aspects resulting from modifications and / or combinations of certain aspects of the present invention based on the following description of the present invention.
  • a liposome is a closed vesicle formed by a lipid bilayer membrane using lipids, and has an aqueous phase (inner aqueous phase) in the space of the closed vesicle.
  • the inner aqueous phase contains water and the like.
  • Liposomes usually exist in a state of being dispersed in an aqueous solution (external aqueous phase) outside the closed vesicles.
  • the liposome composition refers to a composition containing a liposome and an aqueous solution and components contained outside the liposome.
  • Liposomes may be single lamellae (also called monolamellar or unilamellar, and have a double-layered monolayer structure), or may be multilamellar lamellae (also called multilamellar, and a large number of onion-shaped bilayer membranes). And the individual layers are separated by an aqueous layer.) However, in the present invention, from the viewpoint of safety and stability in pharmaceutical use, single lamella liposomes are used. Is preferred. “Encapsulation” means that the liposome takes a form in which the drug is contained in the internal aqueous phase.
  • the average particle size of the liposome is 10 nm to 1000 nm, preferably 20 nm to 500 nm, more preferably 30 to 300 nm, still more preferably 30 nm to 200 nm, 150 nm or less, for example, still more preferably 30 nm to 150 nm, and particularly preferably 70 to 150 nm. preferable.
  • the liposome preferably has a spherical or nearly spherical form.
  • the size (average particle size) of the liposome is preferably substantially 50 to 200 nm, and substantially 50 to 150 nm. Is more preferable, and the diameter is more preferably substantially 50 to 100 nm.
  • the term "substantially” preferably means that at least 75% of the number of liposomes is within the specified diameter. More preferably, said at least 75% is at least 80%, even more preferably at least 90%.
  • the component (membrane component) constituting the lipid bilayer of the liposome contains lipid.
  • Any lipid that is soluble in a mixed solvent of a water-soluble organic solvent and an ester-based organic solvent can be used arbitrarily.
  • Specific examples of lipids include phospholipids, lipids other than phospholipids, cholesterols, and derivatives thereof. These components may be composed of a single type or a plurality of types.
  • the liposome in the present invention contains, as constituent components of the liposome membrane, diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterol modified with a hydrophilic polymer.
  • a phospholipid having two acyl chains for example, phosphatidylcholine (lecithin), phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,
  • phospholipids such as sphingomyelin and cardiolipin, and hydrogenated ones thereof (for example, hydrogenated soybean phosphatidylcholine (HSPC)).
  • a phospholipid having two acyl chains is used as a base lipid for forming a lipid bilayer membrane.
  • dihydrosphingomyelin the retention of liposomes in blood can be improved.
  • dihydrosphingomyelin as the base material of the liposome membrane, it is possible to improve the partition property of the liposome membrane and prevent leakage of the encapsulated drug. This is presumed to be because the amide bond of dihydrosphingomyelin has a strong hydrogen bonding ability and interacts strongly with each other to form a strong and highly partitioning film.
  • dihydrosphingomyelin which is completely saturated, has a high melting point and a low mobility of the formed film, and thus sphingomyelin Also, it is presumed that dihydrosphingomyelin can form a membrane having high partition properties.
  • Dihydrosphingomyelin generally has two long-chain alkyl groups in the molecule. One having two long-chain alkyl groups having 16 carbon atoms, and the other having two long-chain alkyl groups having 16 and 18 carbon atoms. And those having a long-chain alkyl group having 16 carbon atoms and 20 to 24 carbon atoms.
  • dihydrosphingomyelin it is preferable to use the following compound having a long-chain alkyl group having 16 or 18 carbon atoms from the viewpoint of preventing leakage of the drug from the liposome. This is because the higher the carbon number, the higher the melting point, and a liposome membrane having a high partitioning property can be produced.
  • dihydrosphingomyelin for example, dihydrosphingomyelin obtained by reducing sphingomyelin derived from a natural product by a general method may be used, or dihydrosphingomyelin obtained by synthesis may be used. Most of dihydrosphingomyelins derived from natural products such as chicken eggs generally have two long-chain alkyl groups having 16 carbon atoms. Therefore, dihydrosphingomyelins having long-chain alkyl groups having 16 and 18 carbon atoms. It is preferable to use those obtained by chemical synthesis in that they can be obtained with high purity.
  • the ratio of dihydrosphingomyelin in the components of the liposome membrane is preferably 30 to 80 mol%, more preferably 40 to 70 mol%, and still more preferably 50 to 60 mol%. is there.
  • hydrophilic polymer in diacylphosphatidylethanolamine modified with a hydrophilic polymer examples include polyethylene glycols, polyglycerins, polypropylene glycols, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, polyvinylpyrrolidone, and synthetic polymers. And polyamino acids.
  • the above hydrophilic polymers can be used alone or in combination of two or more.
  • polyethylene glycols, polyglycerins and polypropylene glycols are preferable from the viewpoint of the blood retention of the composition, and polyethylene glycol (PEG), polyglycerin (PG), polypropylene glycol (PPG) and derivatives thereof are preferred. Is more preferred.
  • polyethylene glycol (PEG) and its derivatives are more preferable.
  • Derivatives of polyethylene glycol (PEG) include, for example, methoxy polyethylene glycol, but are not particularly limited.
  • the molecular weight of the polyethylene glycol is not particularly limited, but is 500 to 10,000 daltons, preferably 1,000 to 7,000 daltons, and more preferably 2,000 to 5,000 daltons.
  • the carbon number of acyl in diacylphosphatidylethanolamine is preferably 16 or more, for example, preferably 16 to 30 carbon atoms, more preferably 16 to 24 carbon atoms, and even more preferably 20 carbon atoms.
  • diacylphosphatidylethanolamine modified with polyethylene glycols examples include 1,2-distearoyl-3-phosphatidylethanolamine-PEG2000 (manufactured by NOF Corporation) and 1,2-distearoyl-3-phosphatidylethanolamine- Examples include 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol such as PEG5000 (manufactured by NOF Corporation) and distearoylglycerol-PEG2000 (manufactured by NOF Corporation).
  • the ratio of diacylphosphatidylethanolamine modified with a hydrophilic polymer is preferably 1 to 15 mol%, more preferably 2 to 10 mol%.
  • Cholesterols include cholesterol having cyclopentahydrophenanthrene as a basic skeleton, part or all of which are hydrogenated, and derivatives thereof. For example, cholesterol is preferred.
  • the curvature of the lipid membrane may increase.
  • the strain of the membrane arranged in the liposome also increases. It is effective to add cholesterol or the like in order to fill the strain of the membrane due to lipid (membrane stabilizing effect).
  • the addition of cholesterol is expected to reduce the fluidity of the liposome membrane by filling gaps in the liposome membrane.
  • the ratio of cholesterol in the constituents of the liposome membrane is preferably 20 mol% to 50 mol%, more preferably 30 mol% to 45 mol%, and further preferably 35 to 43 mol%. %.
  • a hydrophilic polymer or the like for improving the retention in blood a fatty acid or diacetyl phosphate as a membrane structure stabilizer, and ⁇ -tocopherol as an antioxidant may be added.
  • the composition does not contain additives such as dispersing aids that are not approved for use in intravenous injection in pharmaceutical applications, such as surfactants.
  • the liposome composition includes a liposome containing a drug (hereinafter, also referred to as the liposome composition of the present invention).
  • the liposome composition of the present invention contains pharmaceutically acceptable additives, solvents, and the like, if necessary.
  • the type of drug is not particularly limited, and the following anticancer agents can be used.
  • anthracycline anticancer agents such as doxorubicin, daunorubicin and epirubicin; Cisplatin-based anticancer drugs such as cisplatin and oxaliplatin; Taxane anticancer agents such as paclitaxel and docetaxel; Vinca alkaloid anticancer agents such as vincristine and vinblastine; Bleomycin anticancer agents such as bleomycin; Sirolimus anticancer drugs such as sirolimus; Camptothecin-based anticancer drugs such as topotecan (also called nogitecan), irinotecan, karenitesin (registered trademark) (also called BNP1350), exatecan, roototecan, gimatecan (also called ST1481), and verotecan (also called CKD602); Vinca alkaloid anticancer agents such as vincristine; and imatinib (Gleevec (registered trademark)), everolimus (Afinito-act
  • Nogitecan Hydrochloride Chemical name: (+)-(4S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H -pyrano [3 ', 4': 6,7] indolizino [1,2- b] quinoline-3, 14 (4H, 12H) -dione monohydrochloride Can be preferably applied, and an example thereof is Hycamtin (registered trademark).
  • the drug may be used as a salt form.
  • the salt of a drug include salts of a commonly known basic group such as an amino group and an acidic group such as a hydroxyl group and a carboxyl group.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, boric acid, nitric acid and sulfuric acid; formic acid, acetic acid, lactic acid, citric acid, oxalic acid, fumaric acid, maleic acid Salts with organic carboxylic acids such as acids, succinic, malic, tartaric, aspartic, trichloroacetic and trifluoroacetic acids; and methanesulfonic, benzenesulfonic, p-toluenesulfonic, mesitylenesulfonic and naphthalenesulfonic acids And salts with sulfonic acids.
  • mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, boric acid, nitric acid and sulfuric acid
  • formic acid acetic acid, lactic acid, citric acid, oxalic acid, fumaric acid, maleic acid Salts with
  • Salts in the acidic group include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And the like.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethyl
  • the content of the drug in the liposome composition is not particularly limited, but is preferably from 0.025 to 20 mg / ml, more preferably from 0.25 to 10 mg / ml, based on the liposome composition.
  • the molar ratio of the drug contained in the liposome to the lipid forming the liposome membrane is preferably 0.1 to 1.5, 0.2 to 0.3 is more preferable.
  • the release rate of the drug from the liposome increases due to an increase in the area of the liposome membrane per unit amount of the drug, and the function of improving the blood retention property is impaired.
  • the molar ratio of the drug amount to lipid is too high, the osmotic pressure inside the liposome increases due to the increase in the dissolved amount of the drug and the liposome is destroyed, or if the drug precipitates inside the liposome, the The solids grow large and the liposome shape is deformed.
  • the inner aqueous phase of the liposome in the present invention contains ammonium sulfate.
  • the molar ratio of the internal aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more, preferably 0.4 or more.
  • the molar ratio of the internal aqueous phase sulfate ion to the total aqueous phase drug is more preferably 0.4 or more and 1.8 or less, and further preferably 0.6 or more and 1.8 or less.
  • the molar ratio of the internal aqueous phase sulfate to the total aqueous phase drug is too low, the formation of solids due to the sulfate of the drug will be incomplete, and the concentration of the drug in the dissolved state, which increases the permeability of the liposome membrane in the liposome, will be reduced. As a result, the drug easily leaks from the liposome, impairing the effect of improving blood retention.
  • the molar ratio of the internal aqueous phase sulfate ion to the total aqueous phase drug is too high, the osmotic pressure inside the liposome will increase, leading to destruction of the liposome structure. Impair the effect of improvement.
  • the ratio of the sulfate ion contained in the internal aqueous phase of the liposome to the sulfate ion of the entire liposome composition is preferably at least 80%, and more preferably 90% or more. More preferably, at the same time, the ratio of the drug contained in the internal aqueous phase of the liposome to the drug in the entire liposome composition (the internal aqueous phase ratio of the drug) is preferably at least 80%, and more preferably 90% or more. Is more preferred.
  • the drug concentration in the liposome can be measured, for example, by liquid chromatography / ultraviolet-visible absorption detection method.
  • the sulfate ion concentration in the inner aqueous phase of the liposome can be measured, for example, by ion chromatography.
  • the liposome composition of the present invention can include a liposome containing a drug and an aqueous solvent (outer aqueous phase) in which the liposome is dispersed.
  • the pH of the external aqueous phase is preferably neutral, and specifically, is preferably about 5.5 to 8.5.
  • the liposome composition of the present invention has a surprising mechanism of suppressing drug leakage in the blood, delivering a sufficient amount of drug to the tumor, and rapidly releasing the drug in the tumor.
  • the tumor part has a property that the ammonium concentration is higher than that of other organs such as blood and the like (for example, Nanomedicine: Nanotechnology, Biology, and medicinalen, 11 (2015) 1841-1850), and the liposome composition of the present invention
  • the concentration of ammonium is high (5 mmol / L)
  • drug release may be significantly increased.
  • the release rate of a drug from liposomes in plasma having an ammonium concentration of 1 mmol / L or less is 20% / 24 hours or less at 37 ° C., and in a plasma having an ammonium concentration of 4 to 6 mmol / L.
  • the release rate of the drug from the liposome is 60% or more, more preferably, the release rate of the drug from the liposome in plasma having an ammonium concentration of 1 mmol / L or less is 15% / 24 hours or less at 37 ° C.
  • the release rate of the drug from the liposome in plasma at a concentration of 4 to 6 mmol / L is 70% or more.
  • the method for producing the liposome composition of the present invention is not particularly limited, but as an example, (A) preparation of the oil phase; (B) preparation of an aqueous phase; (C) liposome particle formation by emulsification; (D) sizing with an extruder; (E) replacement of the liposome outer aqueous phase solution by dialysis; (F) encapsulation of the drug into liposome particles by remote loading; and (g) removal of the outer aqueous phase drug by dialysis: It can be manufactured by the process of. (D) Sizing by an extruder may or may not be performed.
  • water-soluble organic solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol, glycols such as glycerin, ethylene glycol and propylene glycol, and polyethylene glycol. And polyalkylene glycols. Of these, alcohols are preferred.
  • the alcohol is preferably at least one selected from ethanol, methanol, 2-propanol and t-butanol, more preferably at least one selected from ethanol, 2-propanol and t-butanol, More preferably, it is ethanol.
  • the concentration of each component constituting the liposome is not particularly limited and can be appropriately adjusted.
  • aqueous phase water (distilled water, water for injection, etc.), physiological saline, various buffers, aqueous solutions of saccharides (such as sucrose), and mixtures thereof (aqueous solvents) can be used.
  • aqueous solution of ammonium sulfate it is preferable to use as the aqueous phase.
  • the buffer is not limited to an organic type and an inorganic type, but a buffer having a buffering action near a hydrogen ion concentration close to a body fluid is preferably used, and a phosphate buffer, a Tris buffer, a citric acid A buffer, an acetate buffer, a good buffer and the like can be mentioned.
  • the internal aqueous phase of the liposome may be an aqueous solution in which the liposome is dispersed when the liposome is produced, or may be a newly added aqueous solution of water, physiological saline, various buffers or saccharides, and a mixture thereof. There may be. It is preferable that the water used as the external water phase or the internal water phase does not contain impurities (dust, chemical substances, and the like).
  • Physiological saline refers to an inorganic salt solution adjusted to be isotonic with the human body, and may further have a buffer function.
  • physiological saline include saline containing 0.9 w / v% (mass / volume percent) of sodium chloride, PBS, and Tris-buffered saline.
  • the aqueous phase includes both an external aqueous phase and an internal aqueous phase.
  • the external aqueous phase in the present invention means an aqueous solution in which liposomes are dispersed.
  • a solution occupying the outside of the liposome of the liposome dispersion liquid stored in a vial or a prefilled syringe is the external aqueous phase.
  • the solution occupying the outside of the liposome of the liposome dispersion becomes the external aqueous phase.
  • the inner aqueous phase in the present invention means an aqueous phase in a closed vesicle separating a lipid bilayer membrane of a liposome.
  • an oil phase and an aqueous phase are mixed, and an aqueous solution containing lipids can be emulsified by stirring.
  • an emulsion in which the oil phase and the aqueous phase are emulsified into an O / W type is prepared.
  • some or all of the organic solvent derived from the oil phase is removed by evaporation to form liposomes.
  • part or all of the organic solvent in the oil phase evaporates in the course of stirring and emulsification to form liposomes.
  • ultrasonic or mechanical shearing force is used to make the particles finer. Further, in order to make the particle diameter uniform, an extruder treatment or a microfluidizer treatment through a filter having a fixed pore diameter can be performed. If an extruder or the like is used, the multivesicular liposome formed secondarily can be separated into a unicellular liposome.
  • the emulsification step is not limited as long as it is an emulsification step, but is preferably a step in which high shear is applied and fine particles are formed in an emulsification step containing an organic solvent.
  • High shear is defined by the peripheral speed of the stirring blade of the emulsifier, and is preferably from 5 m / s to 32 m / s, particularly preferably from 20 m / s to 30 m / s. If necessary, the liposome can be formed by evaporating (desolvating) the organic solvent used in the emulsification step.
  • the liquid temperature of the emulsification step when producing liposomes can be appropriately adjusted, but it is preferable that the liquid temperature at the time of mixing the oil phase and the aqueous phase be equal to or higher than the phase transition temperature of the lipid used.
  • the temperature is preferably 35 to 70 ° C.
  • the organic solvent and water may be evaporated from the aqueous solution containing the liposome.
  • Evaporation here means that an organic solvent derived from the oil phase and a part of the water derived from the aqueous phase may be forcibly removed as an evaporation step, or an organic solvent derived from the oil phase and water derived from the aqueous phase may be removed. Some or all of these may spontaneously evaporate in the course of stirring and emulsification.
  • the method of evaporation is not particularly limited.For example, at least one of a step of evaporating by heating an organic solvent and water, a step of continuing standing or gentle stirring after emulsification, and a step of performing vacuum degassing is performed. Just do it.
  • the obtained liposomes can be made uniform in particle size by using a dialysis method, a filtration method, an extrusion treatment, or the like.
  • the extrusion treatment means a process in which a liposome is passed through a filter having pores to apply a physical shearing force to atomize the particles.
  • the liposome dispersion and the filter can be rapidly atomized by maintaining the temperature at or above the phase transition temperature of the membrane constituting the liposome.
  • the sizing by an extruder may or may not be performed.
  • the liposome outer aqueous phase solution may be replaced by dialysis.
  • the dialysate a 0.05 to 5% by mass aqueous NaCl solution can be used, but is not particularly limited.
  • ⁇ (F) Encapsulation of drug into liposome particles by remote loading method it is preferable that the drug is encapsulated in the liposome particles by the remote loading method.
  • the remote loading method refers to a method in which empty liposomes containing no drug are produced, and the drug is introduced into the liposome by adding the drug to the external liquid of the liposome.
  • the method of remote loading is not particularly limited, but a method using an ammonium salt is preferable, and a method using ammonium sulfate is more preferable.
  • the drug added to the external solution is actively transferred to the liposome and is taken into the liposome.
  • a solubility gradient, an ion gradient, a pH gradient or the like is used as the driving force.
  • a solubility gradient, an ion gradient, a pH gradient or the like is used.
  • a proton concentration gradient is generally used.
  • the pH inside (inner aqueous phase) of the liposome membrane is lower than the pH outside (outer aqueous phase).
  • the pH gradient can be specifically formed by a concentration gradient of an ammonium ion gradient or the like.
  • the liposome solution containing the drug may be subjected to dialysis in order to remove the drug not contained in the liposome. For example, by using a sucrose / histidine buffer at a predetermined concentration as a dialysate, the liposome solution containing the drug is dialyzed to remove the drug present in the outer aqueous phase, and the outer aqueous phase is dialyzed. A substituted liposome composition can be obtained.
  • the liposome composition obtained above is preferably subjected to sterile filtration.
  • a filtration method unnecessary substances can be removed from the aqueous solution containing liposomes using a hollow fiber membrane, a reverse osmosis membrane, a membrane filter, or the like.
  • it is preferable to filter with a filter having a pore size that can be sterilized preferably, a 0.2 ⁇ m filtration sterilization filter).
  • the aseptic filtration step and the aseptic filling step described below are preferably performed at a temperature lower than the phase transition temperature of the lipid constituting the liposome.
  • the phase transition temperature of the lipid is around 50 ° C., it is preferably about 0 to 40 ° C., more specifically, about 5 to 30 ° C.
  • the liposome composition obtained after the aseptic filtration is preferably aseptically packed for medical use.
  • Known methods can be applied to the aseptic filling method.
  • a liposome composition suitable for medical use can be prepared by aseptically filling a container.
  • the liposome composition of the present invention may contain at least one of a pharmaceutically acceptable isotonic agent, a stabilizer, an antioxidant, and a pH adjuster in relation to the route of administration. That is, the liposome composition of the present invention can be provided as a pharmaceutical composition.
  • the tonicity agent is not particularly limited, and includes, for example, inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, and sorbitol.
  • inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, and sorbitol.
  • examples include polyols, sugars such as glucose, fructose, lactose, or sucrose.
  • Stabilizers are not particularly limited, and include, for example, saccharides such as glycerol, mannitol, sorbitol, lactose, or sucrose.
  • antioxidants examples include, but are not particularly limited to, ascorbic acid, uric acid, homologs of tocopherol (for example, four isomers of vitamin E, tocopherol ⁇ , ⁇ , ⁇ , and ⁇ ) cysteine, EDTA (ethylenediaminetetraacetic acid), and the like. Is mentioned.
  • the stabilizer and the antioxidant can be used alone or in combination of two or more.
  • pH adjuster examples include sodium hydroxide, citric acid, acetic acid, triethanolamine, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like.
  • the liposome composition of the present invention comprises a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, Pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, phosphorus Acid-buffered saline (PBS), sodium chloride, saccharides, biodegradable polymer, serum-free medium, pharmaceutical additives It may contain additives which are acceptable ones.
  • a pharmaceutically acceptable organic solvent collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl
  • the container for filling the liposome composition of the present invention is not particularly limited, but is preferably a material having low oxygen permeability.
  • light can be shielded by employing a back made of colored glass, aluminum foil, an aluminum vapor-deposited film, or the like.
  • a container filled with the liposome composition it is preferable to replace the gas in the container space and the drug solution with an inert gas such as nitrogen in order to prevent oxidation by oxygen existing in the space inside the container.
  • an inert gas such as nitrogen
  • the injection solution may be bubbled with nitrogen, and the container may be filled under a nitrogen atmosphere.
  • Parenteral administration is preferred as the administration route of the liposome composition of the present invention.
  • Examples include intravenous injection (intravenous injection) such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection.
  • the method of administration includes administration by syringe or infusion.
  • the dose and the number of times of administration of the liposome composition of the present invention may be appropriately set according to the type of drug, the condition of the patient, and the like. / Kg to 100 mg / kg.
  • the mass of the drug as the active ingredient can be set in the range of 2 mg to 10 mg per dose. However, it is not limited to these dosages.
  • a platinum preparation is used as a medicament to be administered simultaneously or sequentially in combination with the liposome composition of the present invention containing a drug.
  • the platinum preparation means a preparation containing a compound containing platinum (platinum) having an anticancer effect as an active ingredient.
  • the platinum preparation can contain a pharmaceutically acceptable additive, solvent, and the like, in addition to a compound containing platinum (platinum) as an active ingredient.
  • Platinum formulations preferred in the present invention include carboplatin, cisplatin, oxaliplatin, nedaplatin, nedaplatin, and miriplatin. In the present invention, one or more platinum preparations can be used. Platinum preparations can be obtained by purchasing commercial products. Examples of preferred platinum formulations in the present invention include carboplatin, cisplatin, oxaliplatin and nedaplatin.
  • Cisplatin (CAS: 15663-27-1) is testicular tumor, bladder cancer, prostate cancer, head and neck cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, stomach cancer, cell lung cancer, osteosarcoma, It is presumed to be effective for cancer types such as liver cancer and biliary tract cancer.
  • carboplatin (CAS: 41575-94-4) is effective in cancer types such as head and neck cancer, small cell lung cancer, testicular tumor, ovarian cancer, cervical cancer, malignant lymphoma, small cell lung cancer, and breast cancer It is speculated that.
  • the dose and frequency of administration of the platinum preparation in the present invention may be appropriately set according to the type of drug, the condition of the patient, and the like.
  • the mass of a drug that is an active ingredient of a platinum preparation can be generally set in the range of 0.01 mg / kg to 100 mg / kg per day.
  • the mass of the drug as the active ingredient can be set in the range of 2 mg to 10 mg per dose.
  • a commercially available platinum preparation it may be appropriately set according to the dose and the number of administrations described in the package insert. However, it is not limited to these dosages.
  • the combination of a drug-encapsulating liposome composition and a platinum preparation is administered simultaneously or sequentially, so that a stronger antitumor effect is obtained as compared with each single agent (drug-containing liposome composition or platinum preparation).
  • a tumor growth inhibitory effect for example, a tumor growth inhibitory effect.
  • the mechanism of action of the combination use of the liposome composition of the present invention and a platinum preparation is presumed as follows, but is not limited thereto.
  • the liposome composition of the present invention has a surprising mechanism of suppressing drug leakage in the blood, delivering a sufficient amount of drug to the tumor, and rapidly releasing the drug in the tumor.
  • Non-Patent Document 2 When a topoisomerase I inhibitor is used in combination, it is presumed that DNA-ISC is hardly removed, the number of cells that induce apoptosis increases, and a synergistic growth inhibitory effect is exerted.
  • the combination of the liposome composition of the present invention and a platinum preparation can inhibit the repair of DNA-ISC for a longer time and strongly, and as a result, the medicament of the present invention dramatically increases the antitumor effect. It is presumed that the drug has low safety concerns.
  • the medicament of the present invention is a medicament administered simultaneously or sequentially by combining a liposome composition containing a drug and a platinum preparation, and can be preferably used as an anticancer agent.
  • the type of cancer to which the medicament of the present invention is applied is not particularly limited.
  • lung cancer particularly, small cell lung cancer
  • ovarian cancer pediatric solid tumor, cervical cancer, breast cancer, prostate cancer, Endometrial cancer, gastric (gastric gland) cancer, non-small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the neck, esophagus cancer, bladder cancer, melanoma, colon cancer, renal cell cancer, non-Hodgkin's lymphoma, Urothelial carcinoma, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, adult T-cell leukemia, bone marrow metastatic cancer, sarcoma, soft tissue tumor, ulcer myelomonocytic leukemia, Hodgkin lymphoma, cutaneous T-cell lymph, and the like.
  • Resistance means that cancer cells show resistance (resistance) to an anticancer drug, which includes natural resistance that the anticancer drug does not work from the beginning of treatment, and initial resistance as treatment continues.
  • An effective anticancer drug refers to a state in which no effect is observed or the effect is diminished. Specifically, it responds initially to an anticancer drug, but then shows a decrease in responsiveness during treatment or that cells continue to proliferate during treatment with the anticancer drug. Indicates a property that did not show an appropriate response to the anticancer agent.
  • the medicament of the present invention can exert an excellent effect on topotecan-resistant cancer.
  • Breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette (ABC) transport protein family. This transport protein directs the efflux of the anticancer drug from the cancer cells, reduces the concentration of the anticancer drug in the cell, and thus reduces or eliminates the desired anticancer effect of the drug on these resistant cancer cells .
  • the drug of the present invention exerts an excellent effect on topotecan-resistant cancer by achieving high-concentration and long-term exposure to topotecan to tumor cells by the EPR effect that is collected and retained in tumor tissue. It is speculated that it can be done.
  • tumor volume in order to measure the tumor volume, the tumor can be transplanted into an animal (preferably mouse or rat) serving as a model.
  • the inhibition of the growth of the tumor volume depends on the drug used, the combination of lipids and the like constituting the liposome, and the effective amount.
  • inhibiting growth of a tumor volume is meant at least one of inhibiting tumor growth, achieving tumor stasis, and substantially or completely regressing the tumor.
  • the model animal When the liposome composition of the present invention is administered to a subject such as a mammal, the model animal is divided into a treatment group and a control group, and the tumor cells are transplanted, for example, in such a manner that 100% of the tumor cells are transplanted so that the tumor cells colonize. It can be started after growing to ⁇ 1000mm.
  • the weight of the whole mouse can be measured every day until the mice of each group reach the minimum weight in order to evaluate the liposome composition of the present invention.
  • Tumors can be measured with calipers or the like until final sacrifice for sampling, until the tumor reaches 2000 mm 3 or until the animal dies.
  • Tumor volume in a mammalian subject can be measured using any art-recognized method. For example, using a caliper measurement, using the formula: (a ⁇ b 2 ) ⁇ 0.5 (where “a” is the maximum diameter and “b” is the length of the minor axis). Tumor volume can be evaluated. In humans, the tumor volume can be measured by a technique such as image diagnosis such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) scanning.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • Chicken egg-derived DHSM means dihydrosphingomyelin (synthetic product obtained by hydrogenating COATSOME NM-10 (manufactured by NOF Corporation) obtained by hydrogenating chicken egg-derived SM.
  • This chicken egg-derived DHSM has two alkyl chains having 16 carbon atoms, which accounts for 70 to 80% of the whole, and the remainder is a mixture containing DHSM having different alkyl chain lengths.
  • Totally synthesized DHSM refers to dihydrosphingomyelin prepared by chemical synthesis so that the following compound having a long-chain alkyl group having 16 and 18 carbon atoms contains 98% or more.
  • DSPE-PEG SUNBRIGHT DSPE-020CN, manufactured by NOF (hereinafter referred to as DSPE-PEG) was used.
  • Cholesterol HP manufactured by Nippon Seika Co., Ltd. was used as cholesterol (denoted as Chol in the table).
  • Aqueous phase 1 was prepared by dissolving 25.2 g of ammonium sulfate in 1118.5 g of water.
  • B2 Preparation of aqueous phase 2 5.04 g of ammonium sulfate was dissolved in 223.7 g of water to prepare aqueous phase 2.
  • (F) Topotecan encapsulation in liposome particles by remote loading Water for injection was added to topotecan hydrochloride (manufactured by Biocompounds) to a concentration of 5 mg / mL. Further, an 8 mol / L HCl solution was added while stirring the solution well, and the pH was adjusted to about 3 to dissolve topotecan. After adding the liposome to this topotecan solution at a volume ratio of 1/1, the mixture was heated at 60 ° C. for 60 minutes.
  • Example 1 Preparation of Oil Phase For Example 1, 11.52 g and 4.32 g of DHSM derived from chicken egg, PEG phospholipid (SUNBRIGHT DSPE-020CN, manufactured by NOF, hereinafter referred to as DSPE-PEG), and cholesterol, respectively. , And 4.32 g.
  • DSPE-PEG PEG phospholipid
  • the amounts of DHSM, DSPE-PEG, and cholesterol were changed to achieve the ratios shown in Table 2. This lipid was mixed with 381 mL of ethanol and dissolved at 65 ° C. to form an oil phase.
  • Aqueous phase 1 was prepared by dissolving 25.2 g of ammonium sulfate in 1118.5 g of water.
  • B2 Preparation of aqueous phase 2 5.04 g of ammonium sulfate was dissolved in 223.7 g of water to prepare aqueous phase 2.
  • Example 9 (A) Preparation of Oil Phase
  • 0.412 g, 0.153 g, and 0.153 g of DHSM, DSPE-PEG, and cholesterol derived from chicken eggs were weighed, respectively.
  • the amounts of DHSM, DSPE-PEG, and cholesterol derived from chicken eggs were changed so as to achieve the ratios shown in Table 2.
  • DiI an amount of DiI of 0.2 mol% based on the total lipid was weighed and dissolved in ethanol. Ethanol was added to this DiI ethanol solution to make the total volume 11.25 mL, and 3.75 mL of ethyl acetate was further added.
  • the weighed lipid and this organic solvent were mixed and heated to 60 ° C. to dissolve the lipid to form an oil phase.
  • the average particle diameter means a cumulant average particle diameter measured by a dynamic light scattering method.
  • the average particle diameter of each of the examples and comparative examples described in the table is a cumulant average particle diameter measured by a dynamic light scattering method using a concentrated particle size analyzer with an autosampler, FPAR-1000AS (manufactured by Otsuka Electronics Co., Ltd.). Tables 1 and 2 show the measurement results.
  • Tables 1 and 2 show the results obtained by measuring the samples and quantifying the concentration of topotecan using an HPLC (high performance liquid chromatography) apparatus Nexera-i LC-2040C (manufactured by Shimadzu Corporation).
  • HPLC high performance liquid chromatography
  • Nexera-i LC-2040C manufactured by Shimadzu Corporation.
  • the specific measuring method is as follows. In the liposomes of Tables 1 and 2, the ratio of the drug contained in the internal aqueous phase of the liposome to the drug in the entire liposome composition was at least 95% except for Comparative Example 10. Comparative Example 10 was 59%.
  • Measurement of the amount of topotecan in the liposome preparation Using a sample solution obtained by dissolving the prepared liposome solution in methanol and filter-filtering, and a calibration curve standard solution prepared by diluting topotecan hydrochloride, measurement was performed by liquid chromatography / ultraviolet-visible absorption detection method. .
  • the inner aqueous phase topotecan concentration was calculated by subtracting the outer aqueous phase topotecan concentration from the total aqueous phase topotecan concentration.
  • the concentration of topotecan in each aqueous phase was measured as follows.
  • sample solution About 50 ⁇ L of a sample (liposome preparation solution) was weighed with Microman (MICROMAN (registered trademark)), and about 950 ⁇ L of methanol weighed with Microman was added thereto. At this time, the solution was shaken for about 1 minute, and it was visually confirmed that the solution became transparent. (2) 100 ⁇ L of the solution of the above (1) was weighed with a Microman, and about 900 ⁇ L of Milli-Q water weighed with a micropipette was added. This solution was shaken for about 1 minute, sonicated for about 1 minute, and further shaken for about 10 seconds.
  • MICROMAN registered trademark
  • the inner aqueous phase sulfate ion concentration was calculated by subtracting the outer aqueous phase sulfate ion concentration from the total aqueous phase sulfate ion concentration.
  • the sulfate ion concentration of each aqueous phase was measured as follows. (Total aqueous phase sulfate ion concentration) 50 ⁇ L of the liposome dispersion was measured and 950 ⁇ L of methanol was added, followed by sonication for 15 seconds and mixing. 90 ⁇ L of the solution was measured, 810 ⁇ L of water for injection (manufactured by Hikari Pharmaceutical Co., Ltd.) was added, and ultrasonic treatment was performed for 30 seconds to mix.
  • aqueous phase sulfate ion concentration 100 ⁇ L of the liposome dispersion was measured and diluted with 900 ⁇ L of a 5% glucose solution (manufactured by Otsuka Pharmaceutical Co., Ltd.). 450 ⁇ L of the solution was subjected to ultrafiltration, and the filtrate was used as an ion chromatography analysis sample. Centrifugation conditions are 7400 g, 5 ° C., and 30 minutes. The centrifugal separator used was a Himac CF15RXII manufactured by Hitachi.
  • the unit of AUC is time ⁇ ng / mL (expressed as hr * ng / mL in the table).
  • the AUC of the liposome described in Non-Patent Document 1 is calculated as 68152 hours x ng / mL.
  • the inner aqueous phase contained ammonium sulfate.
  • the measured value of AUC was 200000 or more, indicating that high blood retention was achieved.
  • Comparative Examples 1 to 8 not using dihydrosphingomyelin Comparative Examples 9 and 10 in which the molar ratio of the internal aqueous phase sulfate ion to the total aqueous phase drug was less than 0.36, and diacylphosphatidylethanol modified with a hydrophilic polymer
  • Comparative Examples 11 and 12 where no amine was used the measured AUC was less than 200,000, indicating inferiority to Examples 1 to 10.
  • composition of Topotecan-encapsulated liposome composition (hereinafter also referred to as topotecan-encapsulated liposome composition or Lipo) of the present invention)
  • Topotecan hydrochloride 20mg HSPC (Note 1) 95.8mg MPEG-DSPE (Note 2) 31.9mg Cholesterol 31.9mg Ammonium sulfate 20mg L-histidine 15.5mg 940mg purified sugar Appropriate amount of pH adjuster
  • the 10 mM histidine / 9.4% sucrose solution is a solution obtained by adjusting the histidine concentration to 10 mM in an aqueous solution of sucrose 9.4 g / 100 mL.
  • Paclitaxel was obtained from Shonan Wako Pure Chemical Company.
  • A2780 cells were obtained from ECACC cell bank.
  • A2780 cells a human ovarian cancer cell line
  • a human ovarian cancer cell line were implanted subcutaneously in the flank of female BALB / cAJcl-nu / nu mice to form subcutaneous tumors.
  • drug treatment was performed using carboplatin alone, Lipo alone of the present invention, a combination of carboplatin and Lipo, and a combination of carboplatin and paclitaxel, and the effect on survival time was evaluated. If the tumor reached 2000 mm 3 and significant deterioration was noted, euthanasia was performed and considered dead.
  • the carboplatin solvent was intraperitoneally administered, and the Lipo solvent was administered once a week via the tail vein for 2 weeks.
  • the carboplatin alone group was administered intraperitoneally once a week for 2 weeks.
  • the Lipo alone group was administered by tail vein once a week for 2 weeks.
  • carboplatin and Lipo carboplatin was administered once by intraperitoneal administration and Lipo was administered once by tail vein administration.
  • carboplatin and paclitaxel carboplatin was administered once by intraperitoneal administration, and paclitaxel was administered once by tail vein administration.
  • Group 1 is a carboplatin solvent and a group administered with a solvent of the topotecan-encapsulated liposome composition of the present invention
  • Group 2 was carboplatin (80 mg / kg)
  • Group 3 is a group administered with the topotecan-encapsulated liposome composition (0.5 mg / kg) of the present invention
  • Group 4 was administered with carboplatin (80 mg / kg) and the liposome composition containing topotecan of the present invention (0.5 mg / kg).
  • Group 5 was administered with carboplatin (80 mg / kg) and paclitaxel (20 mg / kg). did.
  • Groups 1 to 3 and 5 are comparative examples, and group 4 is an example. Table 3 shows the group composition and dosage.
  • Lipo is a topotecan-encapsulated liposome composition of the present invention, intraperitoneal administration in the abdomen, tail vein administration in the tail, administration once a week x2 once a week for two weeks, and one administration during the test period. Administration means respectively.
  • FIG. 1 shows the change in the survival rate of each group.
  • Group 4 showed a significant effect of prolonging survival time compared to Group 1, Group 2, Group 3 or Group 5 (P ⁇ 0.05, stratified Log-rank test). In group 5, death or euthanasia due to worsening condition occurred in 5 out of 8 cases, whereas in group 4, the number of deaths or euthanasia treatments due to worsening condition was 0.
  • the topotecan-encapsulated liposome composition of the present invention when used in combination with carboplatin, significantly survived the topotecan-encapsulated liposome composition of the present invention alone, carboplatin alone or carboplatin, which is the standard treatment for ovarian cancer, in combination with paclitaxel.
  • the period extension effect was shown. High security was also confirmed.
  • a platinum preparation hereinafter, also referred to as carboplatin
  • carboplatin a platinum preparation
  • topotecan-encapsulated liposome composition and topotecan of the present invention were used.
  • carboplatin solvent physiological saline
  • lipo solvent Otsuka Pharmaceutical Factory Co., Ltd. Otsuka Sugar Solution 5%
  • A2780 cells a human ovarian cancer cell line
  • a human ovarian cancer cell line were implanted subcutaneously in the flank of female BALB / cAJcl-nu / nu mice to form subcutaneous tumors.
  • drug treatment with carboplatin alone, Lipo alone of the present invention, topotecan alone, combination of carboplatin and Lipo, and combination of carboplatin and topotecan was performed, and the effect on survival time was evaluated. If the tumor reached 2000 mm 3 and significant deterioration was noted, euthanasia was performed and considered dead.
  • the carboplatin solvent was intraperitoneally administered, and the Lipo solvent was administered once a week via the tail vein for 2 weeks.
  • the carboplatin alone group was administered intraperitoneally once a week for 2 weeks.
  • the Lipo alone group was administered by tail vein once a week for 2 weeks.
  • carboplatin and Lipo carboplatin was administered intraperitoneally once a week for two weeks and Lipo was administered once a week by tail vein for two weeks.
  • carboplatin and topotecan carboplatin was administered once by intraperitoneal administration, and topotecan was administered once a day by tail vein for 5 days.
  • Group 1 is a carboplatin solvent and a group administered with a solvent of the topotecan-encapsulated liposome composition of the present invention
  • Group 2 was carboplatin (80 mg / kg)
  • Group 3 is a group administered with the topotecan-encapsulated liposome composition (0.5 mg / kg) of the present invention
  • Group 4 was administered with topotecan (0.5 mg / kg)
  • Group 5 was administered with carboplatin (80 mg / kg) and the topotecan-encapsulated liposome composition (0.5 mg / kg)
  • Group 6 was administered with carboplatin (80 mg / kg).
  • Groups 1 to 4 and 6 are comparative examples, and group 5 is an example.
  • Table 5 shows the group composition and dosage.
  • Lipo is a topotecan-encapsulated liposome composition of the present invention, intraperitoneal administration in the abdomen, tail vein administration in the tail, once a week x2 once a week for two weeks, once a day x5 once a day x5 Administration means administration for 5 days, and administration means one administration during the test period.
  • Table 6 shows the median survival time calculated from the start of drug administration.
  • FIG. 2 shows changes in the survival rate of each group.
  • Group 5 showed a significant survival time prolonging effect compared to Group 1, Group 2, Group 3, Group 4 or Group 6 (P ⁇ 0.05, stratified Log-rank test). In group 6, death or euthanasia due to worsening condition occurred in 8 out of 8 cases, while in group 5, the number of deaths or euthanasia treatments due to worsening condition was 0.
  • the medicament of the present invention is useful as a medicament for preventing or treating cancer.
  • the administration method of the present invention is useful as an administration method of a medicament for preventing or treating cancer.
  • the treatment method of the present invention is useful as a treatment method for preventing or treating cancer.

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Abstract

La présente invention aborde le problème de la fourniture d'un médicament obtenu par combinaison d'une composition de liposome qui comprend des liposomes encapsulant un médicament avec une préparation à base de platine. L'invention concerne un médicament comprenant une combinaison de : (A) une composition de liposome qui contient, en tant que constituants d'un film de liposome, une diacylphosphatidyléthanolamine modifiée avec un polymère hydrophile, de la dihydrosphingomyéline et du cholestérol, la composition de liposome encapsulant un médicament à l'intérieur de celle-ci, la phase aqueuse interne de celui-ci contient du sulfate d'ammonium, et le rapport molaire de l'ion sulfate dans la phase aqueuse interne à la quantité totale du médicament dans la phase aqueuse interne est de 0,36 ou plus ; avec (B) une préparation à base de platine. Dans le médicament combiné, les composants (A) et (B) sont administrés simultanément ou successivement.
PCT/JP2019/038708 2018-10-01 2019-10-01 Médicament combiné comprenant une composition de liposome encapsulant un médicament et préparation à base de platine Ceased WO2020071349A1 (fr)

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WO2022250013A1 (fr) * 2021-05-24 2022-12-01 富士フイルム株式会社 Agent anti-tumoral
WO2022250015A1 (fr) * 2021-05-24 2022-12-01 富士フイルム株式会社 Agent de traitement
JPWO2022250013A1 (fr) * 2021-05-24 2022-12-01
WO2024111564A1 (fr) 2022-11-21 2024-05-30 富士フイルム株式会社 Médicament combiné comprenant une composition de liposome contenant du topotécan ou un sel de celui-ci encapsulé dans celui-ci et inhibiteur de réparation de dommage à l'adn
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